The present invention relates to a new approach to the delayed or pulsed release of biologically active compounds having pharmaceutical activity, particularly peptides such as INTEGRILIN™, from a polymer matrix. In this system no complicated barrier mechanism is required to prevent the release of the peptide during the lag time, a high loading of the water-soluble peptide is readily achieved, and the length of the delay of the release of the peptide is easily controlled.
Previously, limited release of INTEGRILIN™ was reported from poly(DTH adipate), a member of the tyrosine-derived polyarylates, despite high loadings of the peptide (30% w/w). Subsequent investigations indicated that interactions between the peptide and the polymer were responsible for the minimal release (˜5% of the loaded peptide). Since hydrogen bonding was a component of the interactions, the release of the peptide from poly(DTH adipate) was demonstrated to be sensitive to the pH within the polymer matrix.
The literature is replete with examples of the delayed or pulsed release of active agents using polymeric materials. However, it is possible to divide these systems into two basic categories; those that depend on an environmental stimulus to induce release of the active agent from the polymeric matrix and those that are designed to release the drug after particular intervals of time have elapsed. Examples of environmental stimuli that have been used for this application are electrical impulses, pH or temperature changes, application of magnetic fields, or ultrasound.
Those systems that are time-controlled can further be divided into those that use a barrier technology that is placed around the active agent that is designed to degrade or dissolve after a certain time interval, and those that use the degradation of the polymer itself to induce the release of the active agent.
One approach of this category has been to prepare a polymeric hydrogel composed of derivitized dextran and to incorporate into the hydrogel, a model protein, IgG, with an enzyme, endo-dextranase, that degrades the hydrogel. It was observed that without the enzyme the release of the protein was very slow. However, when the enzyme was included in the formulation, the release rate was dependent on the concentration of the enzyme. At high concentrations, the release was fast and complete. At low concentrations, the release was delayed.
A correlation was found between the delay time and the rate of degradation of the hydrogel. The interpretation of the data was that the mesh size of the hydrogel was too small for efficient diffusion of a large protein molecule such as IgG, but as the enzyme degraded the polymer, the mesh size increased and diffusion was unimpeded.
Delayed release in association with hydrolytic degradation of the polymer has also been investigated. Heller's poly(ortho esters) are viscous ointments at room temperature and when mixed with a model protein, lysozyme, demonstrated a delayed release profile. The length of the delay time was found to correlate with polymer molecular weight and alkyl substituent of the polymer. These experiments, however, are limited by the fact that all of the drug release experiments were conducted at room temperature, perhaps, because the polymers are viscous at room temperature, but not at the physiological temperature of 37° C.
Ivermectin, a water insoluble antiparasitic agent for veterinary applications, was encapsulated in PLGA (50:50) microspheres and the subsequent pulsed release of this agent, in vivo, was shown to be dependant on the degradation rate of the polymer matrix. Pulsed and delayed release of active agents from PLGA microspheres was most intensely studied by Cleland et al. The PLA or PLGA microspheres are processed using a high kinematic viscosity of polymer solution and a high ratio of polymer to aqueous solution. This produces dense microspheres, which require severe bulk erosion to release the drug. These conditions yield microspheres that have low loading (generally 1% w/w), moderate bursts, and lag times during which significant leaching of drug occurs.